A major research emphasis in our laboratory has been to investigate genetic influences on intravenous opioid self-administration behavior in inbred rat and mouse strains. Recent hypotheses regarding the role of innate locomotor activity in the acquisition of drug-reinforced behavior are amenable to testing using this behavior genetics approach. Studies were conducted to investigate the relationship between drug-naive behaviors and the rate of acquisition and extinction of opioid-reinforced behavior. Operant drug-reinforced behavior was examined in a 24 hr access paradigm in which rats received 1 mg/kg/inj of morphine per operant response. The results of these studies suggest large genetic differences in the rate of acquisition and extinction of morphine self-administration that was significantly correlated with baseline locomotor activity. Initial studies using inbred mouse strains confirm these studies and suggest an inverse correlation between the amount of behavior maintained by 1 mg/kg/inj morphine and the potency and rate of tolerance to morphine's analgesic effects in four inbred mouse strains. Additional studies investigating the acute behavioral effects of drugs that may influence subsequent reinforcing properties are being investigated using a chronic drug sensitization paradigm and a conditioned drug effect paradigm. Thus far, pilot studies suggest that sensitization to cocaine's locomotor effects and the conditioned locomotor activity effects of a drug differ in a genotype-dependent manner predictive of self-administration behavior. The biochemical differences underlying vulnerability to acquisition and resistance to extinction of drug self-administration behavior are being pursued in collaboration with Drs. Shippenberg, Heidbreder and Schutz using an in vivo microdialysis technique and Dr. Rothman using a conditioned sensitization paradigm. Naive and morphine-induced efflux of dopamine were compared in two inbred rats strains that demonstrate fast and slow rates of acquisition of morphine self-administration behavior, the Lewis and F344 strains, respectively. Dopamine efflux in the nucleus accumbens of the Lewis rats was relatively unaffected by acute morphine administration as compared to the F344 rats. These data are in contrast to previously reported differences in a randomly outbred rat population.